Targeting the ADA/ADO Axis Rescues β-Cell Failure in Type 2 Diabetes

The progressive decline of functional β-cell mass is a hallmark of type 2 diabetes (T2D), yet no current therapies effectively halt this process. While chronic inflammation and metabolic stress contribute to β-cell dysfunction, the key signals integrating these pathways remain elusive. Circulating adenosine deaminase (ADA) elevation in people with diabetes is often viewed as a bystander effect, not a pathogenic component. Here, we show that this elevation reflects a failed compensatory response in a previously unknown purinergic pathway linking dyslipidemia to β-cell failure. Circulating lipids trigger rapid ATP release from erythrocytes, converted to adenosine (ADO). Accumulated ADO drives tissue-specific ADA upregulation in organs affected by diabetes complications, including spleen, kidney, and islets. When this defense fails, toxic ADO selectively causes apoptosis in macrophages, podocytes, and β-cells via defined mechanisms. We show that exogenous ADA performs systemic clearance and local decompression, boosting circulatory adenosine clearance, normalizing tissue ADA hyperactivity, and rescuing islet immunopathology and function. These findings redefine a fundamental pathogenic circuit in T2D and establish the restoration of ADO homeostasis as a therapeutic strategy capable of producing functional β-cell recovery, thereby positioning disease remission as a mechanistically grounded and attainable goal.